The allergic diseases are caused by an abnormality of the immune system and are caused by the production of particular antibodies of the IgE class, specific towards ubiquitary substances (referred to by the term allergens), per se completely harmless, such as mainly pollens, mites, the epithelial derivatives, the poison of hymenoptera, fungal spores, and several foods. Such IgE antibodies are capable of linking to a specific receptor that is present on the membrane, for example, on the membrane of the mucosal mastocytes, i.e., of the basophiles, and by subsequently reacting with the allergens which they are directed to, are capable of inducing the release of mediators (among which, histamine) by the above-mentioned cells, which mediators are finally the true promoters of the allergic reaction. The allergic symptoms range from rhinitis-conjunctivitis to hives, asthma, up to anaphylactic shock, this latter being an event that can be lethal.
Recent estimates indicate that more than 20% of the population living in the industrialized countries suffers from this type of disease that, persisting in time, can determine, if it not suitably treated, a worsening of the symptoms (for example, appearance of asthma after a rhinitis) and of the sensitization that can extend to other allergens as well, which still more heavily bears on the life quality of those subjects suffering from it, and makes the identification of the more suitable therapeutic remedy to be used in the treatment of the same more complex.
The specific hyposensitization immunotherapy (ITS), unlike the pharmacological therapy, which limits itself to intervene on the symptom that then reappears in the moment when the effect of the drug ceases, is the only form of etiological treatment of the allergic diseases capable of positively bearing on the causes determining the so-called “allergic march” through the activation of some immunological mechanisms that are the basis of the clinical benefit induced by the ITS (Clin Exp Allergy. 2008; 38:1074-88. Update on mechanisms of allergen injection immunotherapy. James L K, Durham S R.; Allergy. 2006; 61 Suppl 81:11-4. Immunological mechanisms of sublingual immunotherapy. Akdis C A, Barlan I B, Bahceciler N, Akdis M.).
ITS consists in the administration in increasing doses of standardized extracts (vaccines), obtained starting from the same substance that causes the disease.
In this manner, a sort of “immunological tolerance” is progressively induced in the patient towards such substance, which is mediated by allergen-specific IgG antibodies, also termed “blocking antibodies”, which, by preventing through a competition phenomenon the antibodies IgE to react with the allergen which they are directed to, inhibit the triggering of the allergic reaction and consequently inhibit the appearance of the symptoms.
The vaccines used for ITS are composed of a quite complex mixture of protein, i.e. glycoprotein, components towards which the specific IgE antibodies that an allergic subject produces are then directed.
Although the therapeutical efficacy of ITS has been shown in a number of clinical studies, it is not free from risks related to the also severe undesired reactions (Immunopharmacol Immunotoxicol. 2008; 30:153-61. Local and systemic reactions occurring during immunotherapy: an epidemiological evaluation and a prospective safety-monitoring study. Ventura M T, Giuliano G, Buquicchio R, Accettura F, Carbonara M.; Immunol Allergy Clin North Am. 2007; 27:295-307 Anaphylactic reactions during immunotherapy. Rezvani M, Bernstein D I; Allergy. 2008; 63:374. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose. Blazowski L.), which can occur following the administration of the vaccine. Such reactions may range from circumscribed local reactions (wheals, flush, itch, etc.) to systemic reactions (reaggravation of symptoms, asthma, to anaphylactic shock); although such risk has been considerably reduced by the use of slow release vaccines (delayed vaccines) or vaccines administered through alternative routes to the injective one, it anyhow limited the use of ITS in the allergic diseases therapy, currently applied on a narrow percentage compared to the entirety of the allergic patients identified following a suitable diagnostic survey.
Food allergies are also strongly increasing. Recently, unlike what has been claimed until a few years ago, whereby the only therapy against these forms of allergy appeared to be represented by the elimination of the suspected food from the diet, the idea is more and more establishing in the allergological field that the option of a specific ITS approach is suitable also for the forms of food allergy. However, it is apparent that the use of native allergens for the therapy of the food allergy forms would have the same limits (risk of undesired effects) found in the ITS of the respiratory allergy forms. In fact, such risks could even be exacerbated, since these forms of allergy often involve subjects having a few months or years of age.
In recent years, a great deal of attention has been focused on the development of vaccines that are more efficient and with a higher safety degree. Particularly, the identification of chemical modification procedures that are more or less selective, yet aimed to reduce the allergenic potential of the vaccines by preservating their immunogenic potential as much as possible, meant as the ability to induce the formation of IgG antibodies capable of recognizing, when administered to the subject, also the unmodified (native) components, which are those to which the allergic subject is exposed, and determining the development of the specific symptoms, lead to the development of the so-called allergoids (J Allergy Clin Immunol. 1985; 76:397-401. Modified forms of allergen immunotherapy. Grammer L C, Shaughnessy M A, Patterson R.; Int Arc hAllergy Appl Immunol. 1971; 41:199-215. Preparation and properties of, allergoids, derived from native pollen allergens by mild formalin treatment. Marsh D G).
The development of allergens also of food origin in the form of allergoid, and the use thereof in the immunotherapy of the specific food allergies could indeed result to be crucial in providing the allergic subject some kind of immunological tolerance, thus avoiding for the subject the occurrence of those reactions which could threaten his/her own life following the unaware ingestion of also minimal amounts of the allergen which he/she is sensitised to.
The degree of reduction of the allergenic potential of an extract induced by chemical modification can be different according to the type of reagent that is used for the modification and/or the type of extract. By using potassium cyanate as a “modifying” reagent, derivatives so-called carbamylated are obtained, which are characterized by a reduced allergenicity and a preserved immunogenicity (Allergy. 1996; 51:8-15. Monomeric chemically modified allergens: immunologic and physicochemical characterization. Mistrello G, Brenna O, Roncarolo D, Zanoni D, Gentili M, Falagiani P.).
However, it shall be noticed that, since the extracts subjected to chemical modification with potassium cyanate are very heterogeneous protein mixtures, the modification degree determined by the dosing of the amino groups is strictly related to the type of protein that is present, therefore the datum which is obtained expresses an average degree of modification degree. In fact, it may happen that some allergenic proteins do not significantly undergo the effect of the modification with potassium cyanate, therefore preserve much of their allergenic activity. At the level of the modified extract, the optional preservation of the allergenic activity by a component of the extract could not be shown. However, different techniques for the purification of the individual allergens have been developed for many years. Therefore, by extending the chemical modification procedure at the level of the single components, today it is possible to point out the substitution degree that can be obtained with potassium cyanate. In the case, for example, of the Der p1 allergen, one of the major allergens of the mite of the species Dermatophagoides pteronyssinus, which is present in the house dust, the modification degree determined by reaction with 2,4,6-trinitrobenzenesulfonic acid (TNBS) does not exceed 50%, compared to a modification degree of the extract of about 80%.